Management of obsessive-compulsive disorder comorbid with bipolar disorder.

Obsessive-compulsive disorder (OCD) is one of the most common comorbidities in bipolar disorder (BD). Clinicians often get perplexed in making treatment decisions when encountering comorbid OCD and BD as treatment of OCD by pharmacotherapy may induce or exacerbate mood instability and psychotherapeutic approaches for OCD may not be feasible in acute manic or depressive state of BD. In this study, we reviewed literature, whether existing guideline-based treatments of BD may be effective in OCD and whether newer agents will be of use for treating this comorbidity. We could find that treatment of such comorbid disorder is largely understudied. Adjuvant topiramate or olanzapine- selective serotonin reuptake inhibitor/clomipramine combination along with mood stabilizer is found to be effective for treating OCD in BD. Use of other conventional pharmacological agents and psychotherapy for treating comorbid OCD in BD lacks evidence and is limited to case reports. Our review also highlights the need for further studies regarding the treatment strategies in this highly prevalent comorbid disorder.

INTRODUCTION

Obsessive-compulsive disorder (OCD) is one of the most frequently associated comorbidities in bipolar disorder (BD).[123] Although the prevalence and impact of OCD in BD are much researched, the neurobiological and treatment aspects are less studied systematically.[34] For clinicians, it is a real challenge to manage patients with BD-OCD comorbidity because both mood stabilizing and management of OCD should go hand in hand. However, the serotonin reuptake inhibitors (SRIs) which are the first-line treatment for OCD can induce manic/mixed mood states in BD. Effects of combined pharmacological treatments and psychotherapeutic treatments are less studied, and no convincing upper hand for a specific modality is observed in OCD comorbid with BD.[356789]

A recent systematic review has described treatment aspects of BD-OCD comorbidity.[4] However, no consensus regarding the best available evidence-based treatment for OCD in manic, depressed, or remitted phases of BD exists. Here, we discuss the current evidence-based treatment of OCD in BD and promising pharmacological methods to manage this complex comorbidity.

EPIDEMIOLOGY

Population-based studies have reported lifetime prevalence rates of comorbid OCD in BD patients ranging between 11.1% and 21%.[1210] In large sample hospital-based studies, the lifetime prevalence of comorbid OCD in BD patients ranged between 3% and 16.3%.[3111213] The prevalence of OCD may be masked by the presence of manic or depressive symptoms in BD which is evident from data in remitted patients where the reported prevalence of comorbid OCD is quite high (35–38.6%).[141516] Lifetime prevalence of BD in OCD is also much higher than that of either OCD or BD and studies show a lifetime prevalence ranging from 6% to 55.8%.[3] Considering all these, we could observe that a significant proportion of BD patients suffer from OCD. The high prevalence of such association is even argued for a specific subtype of BD or OCD or one disorder increasing the propensity to develop the other.

Impact of OCD in BD

The presence of OCD poses a huge impact on morbidity of patients with BD. BD when comorbid with OCD has been associated with greater disability and poorer quality of life,[317] poor functioning,[31318] and higher unemployment[313] in comparison to “pure” OCD or “pure” BD. It is also associated with episodic course,[19] rapid cycling,[17] and more frequent hospitalizations.[3] The presence of OCD positively correlates with time in episode.[16] OCD may add to the high mortality in BD because OCD increasing suicidal ideas and attempts is consistently reported across many studies.[3141720] Comorbid dysthymia,[14] social anxiety disorder,[1321] GAD,[21] substance abuse, and eating disorders[2223] are found to be higher compared to OCD or BD. Polypharmacy and poor treatment response are also documented in BD-OCD comorbidity.[3112425]

Phenomenology

It is very important to differentiate obsessions from depressive ruminations and compulsions from repeated goal-directed activities of mania. Patients with BD show higher levels of rumination even during remission than normal controls.[26] Depressive ruminations are typically about negative events in life and reflect self-criticism, failures, guilt, regret, and pessimism. They are mood-congruent and are not necessarily experienced as intrusive and distressing and are not associated with compulsions as in OCD. Types of obsessive-compulsive symptoms (OCS) in BD are somewhat different from pure OCD Common obsessions in BD-OCD are sexual, agressive and religious obsessions.[3] With regard to compulsions, higher rates of ordering, checking and repeating rituals have been reported.[3]

A recent large sample study showed that OCD is severe in BD-OCD.[13] In comparison to pure OCD, the severity of OCD in BD was significantly higher in a study and was mild to severe on Yale-Brown Obsessive Compulsive Scale (YBOCS).[22] But in a study of remitted bipolar-OCD patients, BD-OCD had less severe OCD compared to pure OCD.[16] Studies on insight into OCD show predominance of poor insight OCD patients in BD-OCD.[3]

NEUROBIOLOGY

Though there are only a few studies on neurobiological aspect of OCD comorbid with BD, we may discuss the possible mechanisms which are of importance for pharmacological treatment.

Neurochemical basis of OCD-BD comorbidity

Serotonin

Only a single study examined the biological marker of BD-OCD comorbidity. The study of serotonin transporter (5-HTT) binding potential using positron emission tomography (PET) and 11C-DASB, a radioligand with high affinity, specificity and reliability for 5-HTT, reported a higher 5-HTT binding potential in drug-free OCD-BD cases as compared to non-OCD-BD in the insula, in the subgenual anterior cingulate cortex, and in the dorsal cingulate cortex. Compared to healthy controls, bipolar subjects showed increased binding potential in insula, thalamus, pregenual anterior cingulate cortex, and dorsal cingulate cortex.[27] In OCD, most of the PET studies using 11C-DASB have shown reduced serotonin transporter binding in thalamus, midbrain, insula, and orbitofrontal cortex.[2829] In a recent meta-analysis of PET and single photon emission computed tomography, studies in major depressive disorder (MDD) documented reduced 5-HTT binding in midbrain and amygdala and; an association between severity of depression and serotonin transporter depletion.[30] We could observe that 5-HTT binding potential in BD-OCD is closer to that of BD and opposite to that of OCD and MDD (i.e., increased in insula, dorsal cingulate just like in BD and decreased in thalamus just opposite of OCD, decreased in midbrain just opposite to MDD). Although only a study documented increased 5-HTT binding potential in bipolar-OCD, it has some therapeutic importance because increased binding potential is associated with homozygosity of long allele of the 5-HTT gene.[3132] Recent studies showed that treatment-emergent mania and rapid cycling are associated with polymorphism of the short allele of 5HTT gene.[33] It can be presumed that BD-OCD may have less chance of mood instability when selective SRI (SSRI) is used to treat OCD in BD.

Glutamate

Glutamate is the main excitatory neurotransmitter and it acts through postsynaptic ionotropic receptors including N-methyl-d-aspartate (NMDA), kainite, and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. Glutamate is important in the pathophysiology of mood disorders and the development of novel AD treatments.[3435] Magnetic resonance spectroscopy permits the investigation of levels of glutamate and glutamine (together known as “Glx”) in specific brain regions in vivo. Increased Glx in left dorsolateral PFC (DLPFC) in mania and in rapid cyclers are documented.[36] Elevated Glx are reported in cingulate gyrus in the manic, mixed, or depressed states of BD subjects.[37] Higher glutamate level in cerebrospinal fluid (CSF) of patients with OCD is also reported.[38] Elevated Glx in caudate,[3940] orbitofrontal white matter,[41] and Glx normalize with medications in OCD.[3942] In two studies, OCS severity correlated with Glx in orbitofrontal white matter and caudate.[4143] Another recent study showed that ACC glutamate is reduced only in “pure” OCD patients without comorbid mood and anxiety symptoms.[38] Overall, we may presume that OCD-BD patients may have increased Glx in caudate, Left DLPFC, reduced Glx in OFC, and normal in ACC.

Although no study has focused on glutamate hypothesis of BD-OCD comorbidity so far, studies of pharmacological interventions targeting glutamate have been in progress, both in BD and OCD. This may help us to formulate a treatment for BD-OCD comorbidity. Lamotrigine, an antiglutamatergic agent which inhibits presynaptic glutamate release, showed significant reduction in Glx in BD[44] and it is an effective drug for bipolar depression.[4546] Lamotrigine augmentation is found to be effective in OCD also.[474849] Riluzole is another agent acting on the glutamatergic system which inhibits glutamate release and enhances of AMPA trafficking and glutamate reuptake.[50] It is found to have AD and anti-obsessive effects.[5152] Memantine is a noncompetitive NMDA antagonist. Memantine has AD, antimanic, and mood-stabilizing properties.[5354] The effectiveness of add-on memantine in OCD is also proven.[55] N-Acetylcysteine (NAC) is a natural amino acid which stimulates inhibitory metabotropic glutamate receptors and thereby reduces the release of glutamate and enhances glial cells’ ability to clear glutamate.[56] In mania/hypomania add-on, NAC may be effective which is evident from a recent systematic review.[57] It is also hypothesized that compulsive behaviors occur due to increased glutamate in the nucleus accumbens.[58] Topiramate may attenuate the regional cortico-striato-thalamo-cortical hyperactivity seen in OCD patients and it is proven to be an effective augmenting agent in OCD and in the study of OCD comorbid with BD.[596061] Hence, we may observe that glutamatergic drugs may be of promising effects in BD-OCD comorbidity.

Dopamine

Increased functional dopamine is postulated as the mechanism underlying mania[62] and BD depression.[63] Lower D1 receptors supporting a hyperdopaminergia is observed in frontal cortex in all the phases of BD[62] and valproate decreased dopaminergic function in manic BD patients.[62] Increased caudate D2 receptor density was observed in psychotic BD patients compared to healthy individuals.[62] Higher striatal dopamine transporter binding was observed in both depressed and drug-free euthymic BD patients.[62] Both typical and atypical antipsychotics used to treat mania have direct and indirect actions on lowering dopamine signaling. ADs, lithium, and valproate also modulate dopamine signaling.[64] Obsessive behaviors are also associated with dysfunction of the dopaminergic receptors. Selective D2/3 receptor antagonist quinpirole induces symptoms associated with OCD in animal models. It is proposed that ritual behaviors are due to hyperdopaminergic state in nucleus accumbens and right PFC.[65] Animal models also show improvement of compulsive behavior by administered D1 receptor antagonist and D1/2 antagonist.[65] These findings are suggestive of the role of dopamine in provoking obsessive behavior.[65] Pharmacological studies also point toward increased dopamine neurotransmission in mania and OCD. Amphetamine increases dopamine and mimic manic symptoms.[62] Methylphenidate or amphetamine also provokes or aggravates the symptoms of OCD.[62] Cocaine, a dopamine transporter blocker that increases the concentration of synaptic dopamine and dopamine transporter, will produce such symptoms similar to OCS.[65] Hypodopaminergia in depression is further supported by effectiveness of dopaminergic agonists - pramipexole and bromocriptine in BD depression and by ability of these agents to induce mania.[62] Reduced CSF levels of homovanillic acid (HVA), a metabolite of dopamine, are documented in BD depression and increased CSF HVA levels are observed during mania.[62] Another aspect of shared neurobiology can be understood from efficacy of antipsychotics in both disorders. In treatment-refractory OCD, serotonin receptor subtypes (5-HT2A, 5-HT2C, 5-HT1A, 5-HT1D, and 5-HT7) are downregulated by chronic SRI use, and consequently, the blockade of serotonin receptors by atypical antipsychotics may potentiate the action of the SRI. SRI-refractory OCD has additional abnormalities in dopaminergic function that requires augmentation with dopamine-blocking agents.[66]

These findings suggest that the serotonin, dopamine, and glutamate may have important role in BD-OCD though not many studies evaluated the neurobiological basis of BD-OCD.

TREATMENT OF OCD COMORBID WITH BD

The research in the treatment aspect of bipolar OCD comorbidity is indeed constrained by the scarcity of placebo-controlled, double-blind studies. However, the priority in management of anxiety disorders in BD is ensuring adequate mood stabilization before considering specific treatments for anxiety symptoms.[767] This “stepwise” approach should be used when selecting primary mood-stabilizer treatments as well as when considering concomitant use of pharmacological or psychological treatment. Though several anticonvulsants and atypical antipsychotics are commonly recommended to treat anxiety disorders including OCD in BD, evidence base is scanty.[7]

Here, we discuss the management of OCD in BD in the contexts of manic, depressive, and remitted phases of BD. Existing evidence and newer possible pharmacological interventions are described.

TREATMENT OF OCD DURING MANIC OR MIXED EPISODE

Many studies reported that obsessive-compulsive symptoms (OCS) decrease during manic or hypomanic state of BD.[68] However, a recent study of large sample size from India reported that more than two-thirds of subjects with this comorbidity have worsening of OCS in manic phase of illness, none of their subjects had improvement in manic phase, and the OCD was severe on YBOCS.[13] During an acute manic or a mixed episode, the treatment of mood symptoms take precedence, and hence, the treatment of OCD can be deferred unless it is very severe.

First-line pharmacotherapies recommended for acute mania as per the Canadian network for mood and anxiety treatment guidelines are lithium, divalproex, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, combinations of lithium/divalproex + risperidone, lithium or divalproex + quetiapine, lithium or divalproex + olanzapine, and lithium or divalproex + aripiprazole.[67] Second-line agents for acute mania include carbamazepine, ECT, lithium + divalproex, asenapine, lithium or divalproex + asenapine, and paliperidone monotherapy.[67] Let us have a look at studies exploring the effectiveness of these drugs or combinations in the treatment of OCD comorbid with BD.

Lithium

There is not even a single case report of improvement of OCD in BD with lithium.[4] Even in pure OCD, adjuvant treatment with lithium is not found to be effective.[6069] There is a question whether episodic OCD is a manifestation of BD, which is raised by report of two cases of episodic OCD remitted with lithium monotherapy.[70] Thus, in BD-OCD, the evidence for lithium use is not yet established.

Valproate

There is a recent case report of successful use of divalproex in the management BD II and OCD after a failed CBT program and the effect lasted for 18 months of treatment with valproate. In the case mentioned, the OCS returned when divalproex was stopped, and reintroduction of divalproex improved OCS.[71] There are reports of successful use of valproate in an SRI intolerant OCD[72] and clozapine-induced OCS.[73] In an eight-week, double-blind, placebo-controlled trial of divalproex sodium in autistic spectrum disorder, there was significant improvement in repetitive behaviors measured by Children's YBOCS in divalproex group and hence it may be useful to treat OCS in BD.[74] There are no controlled trials or open-label studies of valproate in BD-OCD.[4]

Antipsychotic monotherapy

There are no open-label or controlled trials of typical or atypical antipsychotic monotherapy demonstrating efficacy in pure OCD. Clozapine monotherapy was also found to be ineffective in an open-label study of treatment-resistant OCD patients, even in OCD with poor insight. Moreover, there are reports of emergence/exacerbation of OCS with use of atypicals, but in schizophrenia and rare in BD. No report of effect of antipsychotic monotherapy is published so far in BD-OCD.

Risperidone

Risperidone was found to be effective in a recent meta-analysis of double-blind, placebo-controlled trials (DBPCTs) of atypical antipsychotic augmentation in treatment-refractory OCD.[75] There are no studies of risperidone monotherapy in BD-OCD comorbidity. Moreover, a recent systematic review suggests that risperidone monotherapy is not effective in treating comorbid anxiety disorders in BD.[76]

Olanzapine

Olanzapine is reported to have lesser antimanic effect in BD-OCD.[77] A recent systematic review of DBDCTs observed that olanzapine may not be effective as an augmenting agent in OCD.[75] There is a single report of olanzapine-induced OCS in BD on treatment with olanzapine.[78] Many reports of OCS induced by olanzapine in schizophrenia are documented in literature; however, these reports are rare in BD though olanzapine is commonly used in BD.[79]

Quetiapine

No report of quetiapine monotherapy in OCD-BD mania/depression has been published so far. A recent meta-analysis in OCD does not support augmentation with quetiapine.[75]

Aripiprazole

A meta-analysis of two DBDCTs of aripiprazole found that aripiprazole augmentation is effective in treatment-resistant OCD.[758081] No study has been published on the use of aripiprazole in comorbid BD-OCD.

Ziprasidone

In a 12-week open-label study of ziprasidone augmentation of SRI, it was found to be effective in OCD.[82] There is a recent case series of effectiveness of add-on ziprasidone for OCD in schizophrenia. In this report, OCS had been unresponsive to adequate trials of typical antipsychotics, atypical antipsychotics, and SSRIs.[83] No report of use in BD-OCD has been published.

Lithium + quetiapine

In a case of OCD with comorbid BD in manic phase, both OCS and manic symptoms responded to quetiapine 600 mg/day when given with lithium 600 mg/day.[84] Her OCS and BD symptoms were not responded to lithium, carbamazepine, valproate with adjunct typical and atypical antipsychotics and had worsening of OCD with clozapine. Her OCS did not respond even to SSRI and clomipramine.[84] Another case of mixed affective state with OCD responded to lithium 1200 mg/day, valproate, and quetiapine also has been reported.[85]

Valproate + risperidone

Raja and Azzoni reported four cases of mania/mixed state with OCD improved with a combination of valproate (750–900 mg/day) and risperidone (2–4 mg/day).[85] This may be suggestive of anti-obsessive property of low-dose risperidone just like in OCD.[60]

Olanzapine + mood stabilizer

In a case report, addition of olanzapine 15 mg per day to the therapeutic regimen in a BD–OCD patient led to clear improvement in the obsessive-compulsive symptoms over a period of six weeks itself.[86] The therapeutic regimen was not mentioned in the report.

Valproate + aripiprazole

A case of resolution of OCS due to substitution of olanzapine with aripiprazole in a patient on valproate in BD-OCD is also reported.[87]

No report of improvement of OCS with any of the second-line therapy in BD is reported till date except ECT, which will be discussed later.

TREATMENT OF OCD DURING DEPRESSIVE EPISODE

First-line pharmacological agents in BD depression are lithium, lamotrigine, quetiapine, combinations of lithium or divalproex + SSRI, olanzapine + SSRI, lithium + divalproex, lithium or divalproex + bupropion.[6788] Second-line options include Quetiapine + SSRI, divalproex, lithium or divalproex + lamotrigine, and adjunctive modafinil.[67]

Efficacy of lithium for OCD with BD depression is yet to be explored[4] and even in pure OCD, adjuvant treatment with lithium is not found to be effective.[6069]

Lamotrigine

A recent DBDCT showed that lamotrigine augmentation (100 mg/day) of SSRI is found to be effective in treatment-resistant OCD over 4 month period.[47] An open-label trial of lamotrigine (up to 200 mg/day) add-on treatment for OCS was found be effective in OCD-schizoaffective disorder comorbidity but not in schizophrenia-OCD comorbid subjects.[48] The beneficial effect of lamotrigine (up to 150 mg/day) added to clomipramine (225 mg/day) in a patient with treatment-resistant OCD was also reported.[49]

Described above.[75]

Lithium/valproate + selective serotonin reuptake inhibitor

Antidepressants (AD), especially serotonin-reuptake inhibitors and serotonin-norepinephrine-reuptake inhibitors, are used effectively in the treatment of OCD. However, these ADs are known to cause mood instability in BD. Till date, no study has examined the risk and correlates of treatment-emergent affective switch (TEAS) in BD-anxiety disorder comorbidity.[6789] Because anxiety disorders generally are associated with chronic course, long-term AD use may have risk of illness destabilization compared with short-term use for discrete episodes of depression. Moreover, most of the AD trials for BD depression have not reported on the impact of treatment on comorbid anxiety symptoms disorder though many of these AD trials had a sample size sufficient to explore this issue. There are no studies specifically focusing on patients with BD and a specific comorbid anxiety disorder.[909192] Although there no controlled trials, ADs are commonly prescribed to BD patients for treating anxiety symptoms. A large epidemiologic study found presence of a comorbid anxiety disorder to be the strongest predictor of AD use among patients with BD, even more than the presence of depressive episodes, and most were receiving AD monotherapy, rather than in combination with antimanic medications.[93] Similarly, in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) clinical sample, BD patients with comorbid anxiety disorder were more likely to receive treatment with an AD than BD patients without anxiety.[94] A recent meta-analysis analyzing the TEAS in BD found that the risk of mania with/without AD was 12.5% and 7.5%, respectively.[95] Tricyclic ADs (TCAs) and venlafaxine were associated with a high risk of TEAS compared to SRIs. Surprisingly, mood stabilizers were not found to have mania-limiting effect when given in combinations with ADs.[95] Hence, judicious use of ADs is needed in bipolar depression with OCD as mood instability is more likely because AD dose required to treat OCD is much higher than that of depressive disorder. Adding to the complexity, there are no studies exploring whether switch depends on the dose of ADs or speed of titration and whether it varies within a class of drugs itself.[95] A few cases have been reported with effective use of paroxetine (40 mg/day), clomipramine, escitalopram for OCD in BD in the absence of mood stabilizer, but inducing switch.[85] The worsening of OCS is reported with use of sertraline in a case of BD-OCD.[85] Switch to hypomania/mania/mixed state on treatment for OCD in BD is documented with the use of paroxetine under cover of lamotrigine, venlafaxine,[71] and escitalopram.[718596] In general, it is recommended to use ADs cautiously and under the cover of a mood stabilizer in BD-OCD just as recommended in BD depression.[93]

Olanzapine + selective serotonin reuptake inhibitor

An open-label trial of olanzapine augmentation of SRI in OCD with poor insight, with more than half of subjects with BD showed significant differences in YBOCS and MADRS at 12 weeks and the effect was noticed up to one year of olanzapine (6.9 ± 4 mg/day) treatment[97] [Table 1]. This may add to the sparse evidence-based treatment of BD-OCD.

Table 1

Treatment studies of OCD comorbid with BD

Lithium + divalproex

In the largest study of BD-OCD, 42.1% of BD–OCD patients required a combination of multiple mood stabilizers (lithium plus antiepileptic), and 10.5% were treated with mood stabilizers plus neuroleptic agents (clozapine, olanzapine, and risperidone).[24] The same study did not compare OCS severity between different treatment groups.

Quetiapine + selective serotonin reuptake inhibitor

No report has been published till date.

Adjunctive modafinil

Add-on modafinil 200 mg/day to escitalopram 40 mg/day in a case of OCD resulted in a significant improvement but when increased further to 400 mg/day developed mania on the very next day of increasing the dose.[101] Two other cases also reported worsening of OCD when added modafinil 100 mg/day to SSRIs.[102] Hence, from existing literature, it is better to avoid modafinil in BD-OCD.

Valproate + lithium + risperidone

A case of severe depression with psychotic symptoms and OCD in a patient with BD responded with combination treatment with lithium 750 mg/day, valproate 800 mg/day, and risperidone 4 mg/day.[85]

Till date, no report of combination of Lithium or divalproex + bupropion, lithium, or divalproex + lamotrigine in BD depression-OCD has been published so far.

BD IN REMISSION WITH OCD

Highest prevalence of OCD in BD is documented in studies of remitted patients.[3] In remitted cases of BD, clinicians will be hesitant to start a SSRI because of high propensity of SSRI to induce mood instability. Only two cases of use of aripiprazole for OCD in remitted patient with BD are reported.

Aripiprazole 15 mg/day when added to ongoing lithium 900 mg/day OCD responded in 4 weeks in a case of BD-OCD.[87] Uguz also reported a BD patient in remission with active OCS responded with change of olanzapine to aripiprazole 25 mg/day along with ongoing valproate 1000 mg/day.[87]

EXPERIMENTAL TREATMENTS OF OCD IN BD

Topiramate

A recent DBDCT examined the efficacy and safety of adjuvant treatment with topiramate for subjects with bipolar mania and OCD[61] [Table 1]. Both groups received lithium, olanzapine, and clonazepam. Topiramate group had greater improvement in YBOCS score and no serious adverse effects were detected at 4 months of treatment. This is the only DBDCT of any drug in OCD-BD comorbidity till date.[61] Topiramate augmentation in OCD is supported by a few DBDCTs. In a placebo-controlled randomized trial, SSRI augmentation with topiramate (mean dosage: 180 mg/day) in treatment nonresponders resulted in a mean decrease of 32.0% in YBOCS score, compared with a 2.4% decrease for those receiving placebo.[103] Another 12-week, double-blind, placebo-controlled, parallel-group trial of topiramate augmentation of SSRI demonstrated improvement in compulsions, but high rate of adverse events was observed in topiramate group.[5960] There are case reports of topiramate augmentation of SSRI being effective in OCD.[104]

Memantine

Antimanic property of memantine (10–30 mg/day) is documented in open-label add-on treatment with mood stabilizers in bipolar mania.[54107] Another multicenter open-label trial also established antimanic effect of memantine.[108] A case of bipolar II hypomania improved with memantine 20 mg/day and valproic acid 450 mg/day is reported.[109] Memantine may be an effective augmenting agent in OCD also. In a DBRPCT of memantine, add-on to fluvoxamine OCD improved significantly.[55] In a single-blind, case-control study of add-on memantine (5 mg/day–18 mg/day) in 22 severe OCD patients receiving standard intensive residential treatment (IRT) with both CBT and drug treatment,[110] memantine group showed significantly more improvement than IRT group and no drug group. An open-label 12-week augmentation trial of memantine (up to 20 mg/day) in SSRI- and atypical antipsychotic augmentation-resistant patients with OCD showed significant improvement.[111] Case reports of effectiveness of citalopram and memantine 5 mg/day[112] and memantine along with citalopram and CBT are reported.[113] No manic switch or worsening of BD with memantine has yet been reported.[114]

A recently published double-blind placebo-controlled study of 8-week memantine versus placebo added on ongoing lamotrigine showed only an early, transient AD effect in bipolar depression during at week 4, but no effect at week 8.[53] Lamotrigine and memantine combination may be effective in BD-OCD because each of these have anti-obsessional action. Memantine + valproate are found to be effective in bipolar depression with OCD in a case.[109]

Riluzole

Two open-label trials and a case series describe effectiveness of riluzole (50–100 mg/day) augmentation of SSRI in OCD.[5152115116117] In reported studies of riluzole in OCD, riluzole is highly effective in hoarding symptoms.[115117] In an open-label study, riluzole (100–200 mg/day) was effective in bipolar depression when added to lithium.[52118119] However, no report of use of riluzole in mania has been published so far.[52118] Further studies are needed to confirm its use in BD-OCD.

N-Acetylcystiene

Effectiveness of NAC is reported in OCD and OC spectrum disorders.[120] In BD depression and mania/hypomania, add-on NAC is effective which is evident from recent systematic reviews.[57121122123] Hence, combination of NAC with mood stabilizer treatment may be of use in BD-OCD; however, no controlled studies/open-label trials/case reports studies are published yet in comorbid BD-OCD.

Benzodiazepines

Although widely used, the evidence for benzodiazepines in anxiety disorders with BD is very low.[7] In OCD, clonazepam has been found to be ineffective as an augmenting agent or monotherapy in RCTs.[105106] Benzodiazepines are used as “rescue medications” in many trials of mood stabilizers, but its effects on comorbid anxiety disorder are not studied.[7] No studies have evaluated the efficacy and safety of benzodiazepines in BD-OCD, and hence, benzodiazepines should be used in BD-OCD only after assessing the risk of dependence.

Electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation and psychosurgery

Electroconvulsive therapy (ECT) is documented to be efficacious in manic, depressed, and mixed states of BD and in a few cases of OCD.[124125] There are reported cases of BD-OCD[126] and schizoaffective disorder-OCD[127] improved with ECT. Hence, ECT may be of some use in acute manic/depressed bipolar patients with comorbid OCD.

Current evidence suggests that transcranial magnetic stimulation (TMS) may have a role in OCD and bipolar depression but large controlled trials are needed to confirm its efficacy.[128] TMS may be a promising treatment in future for BD-OCD if we find it effective in further researches as it is a noninvasive procedure.[129] Deep brain stimulation (DBS) is still an experimental treatment for OCD.[130] A case of BD-OCD whose OCD symptoms improved, but manic symptoms worsened with DBS of bilateral anterior limbs of the internal capsules is reported.[131] Although there are reports of improvement in OCD with psychosurgery, there are no reports in BD.

Psychological interventions for OCD in BD

Psychological interventions have become an integral part of treatment in OCD. Meta analyses of cognitive behavioral therapy (CBT) in OCD have shown it to be effective.[132133]

No controlled/open-label trial of CBT alone or in combination with pharmacotherapy in BD-OCD has been published so far. Two cases of BD well controlled on lithium and neuroleptics showed long-lasting improvement up to a year for OCD with biweekly behavioral therapy are reported.[99] Another case of mania with OCD responding to BT in four weeks on lithium treatment is reported.[98] In another case, BD patient responded well to high doses of escitalopram (40 mg/day) added to divalproex along with psychoeducation with behavioral intervention. Surprisingly, in a case of BD-OCD, the OCD failed to CBT and later responded to divalproex monotherapy.[71] In another case, BD patient responded well to high doses of escitalopram (40 mg/day) added to divalproex along with psychoeducation with behavioral intervention.[100] Hence, we may conclude that CBT can be integrated to the treatment of BD disorder patients in comorbid OCD.

But, there are issues like reduced efficacy of CBT in depression and non-feasiblity in mania.[99134] In a recent systematic review, hoarding, increased OCD symptom severity, OCD symptom subtypes such as obsessions of religious, sexuality, symmetry, and arranging compulsions were associated with poor psychological treatment outcome.[135] These features are more common in BD-OCD.[3] Moreover, poor CBT response predictors such as poor insight into OCS[136137] and comorbid anxiety disorders[132122] are seen in OCD when associated with BD, and hence, the therapy response may be poor in BD-OCD. But, in remitted BD patients with OCD, psychotherapy for OCD can be tried as the first line treatment before modifying the medications.

Summarizing, the trials in BD-OCD comorbidity support the use of topiramate and olanzapine-SRI along with valproate. Treatment studies on OCD in BD are summarized in Table 1. Although much researched in OCD and BD, approaches such as use of memantine, riluzole, TMS, and cognitive behavioral therapy are still in experimental stages for management of BD-OCD comorbidity. Many other factors such as drug interactions, availability of therapist, and affordability for interventions are also to be considered. When analyzing the treatment studies on this topic, we should consider potential publication bias for the studies favouring an intervention, because negative trials and cases published are very few in number. Although a few researches are conducted on prevalence and impact of OCD in BD, further intervention studies would help to provide the better treatment for patients with BD-OCD.

CONCLUSIONS

Treatment of comorbid BD with OCD is a huge challenge for clinicians as the management of one disorder may worsen the other and researches into the treatment aspects of this entity is sparse. Mood stabilizers along with adjuvant topiramate or with olanzapine-SSRI/clomipramine combination can be used to treat OCD in BD. Evidence for use of other conventional agents used in BD for treating comorbid OCD is limited to case reports.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.